Current approaches for assessing molecular endpoints in certain diseases usually require tissue and blood sampling, surgery, and in the case of experimental animals, sacrifice at different time points. Despite improvements in non-invasive imaging, more sensitive and specific imaging agents and methods are needed. Imaging techniques capable of visualizing specific molecular targets and/or entire pathways would significantly enhance our ability to diagnose and assess treatment efficacy of therapeutic interventions for many different disease states. Most current imaging techniques report primarily on anatomical or physiological information (e.g., magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound). Newer modalities such as optical imaging and new molecular imaging probes have the potential to revolutionize the way disease is detected, treated, and monitored.
A common paradigm for molecular imaging involves the use of a “molecular” probe or agent that selectively targets a particular gene, protein, receptor or a cellular function, with the absence, presence, or level of the specific target being indicative of a particular disease state. In particular, optical imaging offers several advantages that make it a powerful molecular imaging approach, both in the research and clinical settings. Optical imaging can be fast, safe, cost effective, and highly sensitive. Scan times are on the order of seconds to minutes, there is no need for ionizing radiation, and the imaging systems can be simple to use. In addition, optical probes can be designed as dynamic molecular imaging agents that may alter their reporting profiles in vivo to provide molecular and functional information in real time. In order to achieve maximum penetration and sensitivity in vivo, the choice for most optical imaging in biological systems is within the red and near-infrared (NIR) spectral region (600-900 nm), although other wavelengths in the visible region can be used. In the NIR wavelength range, absorption by physiologically abundant absorbers such as hemoglobin or water, as well as tissue autofluorescence, is minimized.
Prostate cancer is the sixth leading cause of cancer-related death in the world; it is the second leading cause of cancer-related death in the United States. Prostate cancer develops in the prostate, a gland of the male reproductive system. While it can be aggressive, most forms are slow growing cancers. Metastasis, or spreading, of the cancer may occur in other parts of the body such as the bones and lymph nodes. Prostate cancer can cause symptoms such as difficulty during urination, frequent urination, increased nighttime urination, blood in the urine, painful urination, erectile dysfunction, problems during sexual intercourse, and pain.
Prostate Specific Antigen (PSA) is a protein produced by cells of the prostate gland. PSA was the first identified prostate antigen and has become a premier tumor marker for diagnosis, monitoring, and prognosis of prostatic carcinoma. Prostate specific antigen serves as a molecular target for novel active and passive immunotherapy currently under investigation.
PSA is not found in significant levels in tissues outside the prostate gland. Under normal conditions, high concentrations of PSA are stored in the prostatic ductal network. Disruption of the normal tissue architecture in the prostate or distal sites by prostate cancer cells causes leakage of increased amounts of PSA into the tissue interstitium and then the circulation.
Though PSA is used to screen for prostate cancer, a patient's serum PSA level alone does not provide enough information to distinguish benign prostate conditions from actual cancer of the prostate. Furthermore, there are several issues regarding the use of PSA as a target for therapy. First, it is secreted and present in high concentrations in the serum. This can block targeting to tumor cells before a therapeutic or diagnostic agent can bind or enter the cancer cell. Second, PSA is expressed at lower levels in hormone-resistant cancer.
One complication to effective prostate cancer screening is the existence of multiple forms of the PSA protein. Within the prostate, peptidases remove amino acid sequences from the immature PSA protein to create the mature, enzymatically active form of the PSA protein. Enzymatically active PSA is only present in prostate tissue. Enzymatically inactive variants of PSA are created when the immature protein is not properly processed. Standard diagnostic tests do not distinguish between enzymatically active and inactive forms of PSA. Small quantities of enzymatically active PSA leak out of the prostatic ductal network into circulation. High serum levels of the enzymatically active form of PSA are only found during prostate cancer. Once in circulation, the active PSA forms complexes with the serum protease inhibitor alpha-1-antichymotrypsin (ACT), while the enzymatically inactive forms remain unbound. The combined totals contribute to the low levels that can be measured in the circulation. High levels of complexed (and therefore enzymatically active) PSA are more likely indicative of the presence of cancer. Targeting the enzymatically active form of PSA would lead to more reliable prostate cancer diagnoses.
Long term survival from cancer is highly dependent upon early detection and treatment. The ability to detect different patterns of protein expression in healthy versus abnormal prostate tissue can help classify early prostate changes that could lead to cancer. The ability to more accurately and efficiently detect and quantify levels of mature prostate specific antigen will aid in the understanding of pathogenesis and prognosis of prostate cancer, as well as in the determination of the most appropriate treatment regimens.